1. Field of the Invention
The present invention relates to host immune factors and antibiotics and, more particularly, to a system and method for controlling and reducing the antibiotic tolerance of bacterial persister cells with host immune factors.
2. Description of the Related Art
Recent research has shown that persister cells play important roles in intrinsic antibiotic resistance of bacteria. Persister cells are a small subpopulation of dormant phenotypic variants, which can be found in many bacterial species. The dormant nature of persister cells allows this subpopulation to survive the attack of almost all classes of antibiotics. Thus, when an antibiotic therapy is stopped, the surviving persisters relapse to normal cells causing chronic infections with recurring symptoms. Persister formation increases in biofilms, which are complex communities of cells that grow on surfaces and protected by an extracellular polysaccharide matrix secreted by attached cells. Although the majority of biofilm cells can be killed by antibiotics, surviving persister cells serve as seeds for regrowth of the biofilm after an antibiotic treatment. Furthermore, owing to the extracellular polysaccharide matrix, penetration of antibiotics into the biofilm is hindered and the access to the cells is reduced. Thus, the persister cells and exopolysaccharide matrix play important roles in biofilm-associated drug resistance.
It has been observed that the clinical isolates of Pseudomonas aeruginosa in the airways of cystic fibrosis patients produces more biofilm-like microcolonies, harboring drug tolerant persister cells. The dormancy and antibiotic tolerance of persister cells and their capabilities to relapse to normal cells pose a major therapeutic challenge to the treatment of infectious diseases (10). To address this grand challenge, it is important to develop new therapies that can reduce the antibiotic tolerance of persister cells.
During bacterial infection, the human immune system coordinates many types of cells and molecules to eliminate the invading pathogen. The host innate immunity acts as the first line of defense to block the entry of pathogens and kill the microbes that successfully penetrate the epithelial barrier. Innate immune system also activates the adaptive immunity, that is more specific against the invading species and provides long-term protection by developing antibodies and memory lymphocytes. During innate immune response, macrophages and dendritic cells secrete cytokines, which are signaling proteins acting as mediators to attract more immune cells, such as phagocytes. The cytokines can be classified into subgroups such interleukins, tumor necrosis factors, interferons, colony simulating factors, transforming growth factors and chemokines. These cytokines have important functions in regulating the host responses to infections and inflammations. Macrophages secrete various cytokines like IL-1, IL-6, IL-8, IL-10, IL-11, IL-12, IL-15 TNF-α, IFN-α, -β, M-CSF, GM-CSF, G-CSF, etc. Among them, GM-CSF (granulocyte macrophage-colony stimulating factor), secreted by macrophages in response to microbial pathogens, participates in the survival and activation of macrophages, neutrophils, eosinophils and maturation of dendritic cells. Increase in the level of GM-CSF helps recruit monocytes/macrophages to the sites of infection. The receptor for GM-CSF, CD116 is expressed on the hematopoietic cells and is composed of specific α chain and β chain. GM-CSF binds to the α chain with low affinity, but binding to the β chain causes dimerization of both α and β subunits. This dimerization increases the binding affinity of GM-CSF to its receptor, which leads to receptor activation resulting in stimulation of JAK2 (Janus Kinase 2) pathway. The JAK2 protein is for controlling the production of blood cells from hematopoietic stem cells. It is observed that under normal conditions, the level of GM-CSF in the circulation is below 0.35 pM, but it increases as a response to P. aeruginosa lipopolysaccharide (LPS), which is a major component of the outer membrane of this microbe and contributes to its virulence. The response of alveolar macrophage to LPS purified from P. aeruginosa in (GM-CSF)-deficient (GM−/−) and wild type (GM+/+) mice has been studied, and it was observed that GM-CSF is required for the alveolar macrophage response to LPS by stimulating expression of a specific subset of components of the Toll-like receptor 4 (TLR-4). TLR-4 is a protein which detects the LPS of Gram-negative bacteria.
Description of the Related Art Section Disclaimer: To the extent that specific patents/publications are discussed above in this Description of the Related Art Section or elsewhere in this Application, these discussions should not be taken as an admission that the discussed patents/publications are prior art for patent law purposes. For example, some or all of the discussed patents/publications may not be sufficiently early in time, may not reflect subject matter developed early enough in time and/or may not be sufficiently enabling so as to amount to prior art for patent law purposes. To the extent that specific patents/publications are discussed above in this Description of the Related Art Section and/or throughout the application, they are all hereby incorporated by reference into this document in their respective entirety(ies).